Soluble TNF mediates amyloid-independent, diet-induced alterations to immune and neuronal functions in an Alzheimer's disease mouse model.
Soluble TNF mediates amyloid-independent, diet-induced alterations to immune and neuronal functions in an Alzheimer's disease mouse model.
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DOI：
10.3389/fncel.2023.895017
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发表时间：
2023
影响因子：
5.3
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中科院分区：
文献类型：
--
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简介：越来越多的证据表明，包括阿尔茨海默病 (AD) 在内的神经退行性疾病是基因与环境相互作用的产物。免疫系统是介导这些相互作用的主要贡献者。外周免疫细胞与中枢神经系统 (CNS) 微脉管系统和脑膜、血脑屏障和肠道内的细胞之间的信号传导可能在 AD 中发挥重要作用。细胞因子肿瘤坏死因子 (TNF) 在 AD 患者中升高，调节大脑和肠道屏障的通透性，由中枢和外周免疫细胞产生。我们的小组之前报道过，可溶性 TNF (sTNF) 调节细胞因子和趋化因子级联，从而调节年轻 5xFAD 雌性小鼠的外周免疫细胞向大脑的运输，并且在单独的研究中，高脂肪和高糖饮食 (HFHS) 会失调信号通路，从而触发 sTNF 依赖性免疫和代谢反应，从而导致代谢综合征，而代谢综合征是 AD 的危险因素。我们假设 sTNF 是外周免疫细胞对基因与环境相互作用、AD 样病理、代谢功能障碍和饮食引起的肠道菌群失调的关键介质。方法：雌性 5xFAD 小鼠接受 HFHS 饮食 2 个月，然后最后一个月给予抑制 sTNF 的 XPro1595 或盐水载体。我们通过多色流式细胞术对从大脑和血液中分离的细胞的免疫细胞谱进行了量化；还对脑切片进行了代谢、免疫和炎症 mRNA 和蛋白质标记物生化和免疫组织学分析、肠道微生物组和电生理学分析。结果：在这里，我们发现通过生物制剂 XPro1595 选择性抑制 sTNF 信号传导可以调节 5xFAD 小鼠的 HFHS 饮食对外周和中枢免疫特征的影响，包括 CNS 相关 CD8+ T 细胞、肠道微生物群的组成和长期增强缺陷。讨论：致肥饮食会诱导 5xFAD 小鼠的免疫和神经元功能障碍，而 sTNF 抑制可减轻其影响。需要对因遗传易感性和与周围炎症合并症相关的潜在炎症而面临 AD 风险的受试者进行临床试验，以调查这些发现在多大程度上转化为临床。
Introduction: Increasing evidence indicates that neurodegenerative diseases, including Alzheimer’s disease (AD), are a product of gene-by-environment interplay. The immune system is a major contributor mediating these interactions. Signaling between peripheral immune cells and those within the microvasculature and meninges of the central nervous system (CNS), at the blood-brain barrier, and in the gut likely plays an important role in AD. The cytokine tumor necrosis factor (TNF) is elevated in AD patients, regulates brain and gut barrier permeability, and is produced by central and peripheral immune cells. Our group previously reported that soluble TNF (sTNF) modulates cytokine and chemokine cascades that regulate peripheral immune cell traffic to the brain in young 5xFAD female mice, and in separate studies that a diet high in fat and sugar (HFHS) dysregulates signaling pathways that trigger sTNF-dependent immune and metabolic responses that can result in metabolic syndrome, which is a risk factor for AD. We hypothesized that sTNF is a key mediator of peripheral immune cell contributions to gene-by-environment interactions to AD-like pathology, metabolic dysfunction, and diet-induced gut dysbiosis. Methods: Female 5xFAD mice were subjected to HFHS diet for 2 months and then given XPro1595 to inhibit sTNF for the last month or saline vehicle. We quantified immune cell profiles by multi-color flow cytometry on cells isolated from brain and blood; metabolic, immune, and inflammatory mRNA and protein marker biochemical and immunhistological analyses, gut microbiome, and electrophysiology in brain slices were also performed. Results: Here, we show that selective inhibition of sTNF signaling via the biologic XPro1595 modulates the effects of an HFHS diet in 5xFAD mice on peripheral and central immune profiles including CNS-associated CD8+ T cells, the composition of gut microbiota, and long-term potentiation deficits. Discussion: Obesogenic diet induces immune and neuronal dysfunction in 5xFAD mice and sTNF inhibition mitigates its effects. A clinical trial in subjects at risk for AD due to genetic predisposition and underlying inflammation associated with peripheral inflammatory co-morbidities will be needed to investigate the extent to which these findings translate to the clinic.
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影响因子：
2.1
作者：
Giudetti, Anna Maria;Romano, Adele;Gaetani, Silvana
通讯作者：
Gaetani, Silvana
影响因子：
48
作者：
Callahan BJ;McMurdie PJ;Rosen MJ;Han AW;Johnson AJ;Holmes SP
通讯作者：
Holmes SP
影响因子：
4.3
作者：
de Paula GC;Brunetta HS;Engel DF;Gaspar JM;Velloso LA;Engblom D;de Oliveira J;de Bem AF
通讯作者：
de Bem AF
影响因子：
56.9
作者：
Beattie, EC;Stellwagen, D;Malenka, RC
通讯作者：
Malenka, RC
影响因子：
15.5
作者：
Lagkouvardos, Ilias;Lesker, Till R.;Clavel, Thomas
通讯作者：
Clavel, Thomas